Exploring the gut microbiota of breast cancer patients

Teng, Nancy (2023) Exploring the gut microbiota of breast cancer patients. Doctoral thesis, University of East Anglia.

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Host-associated microbial communities play a key role in health and disease, and more recently there has been a growing appreciation for how particular microbes and microbial ‘signatures’ are associated with different cancers. However, breast cancer remains an understudied cancer type, and there is a pressing need to define, if and how, the gut microbiota maybe be linked to disease progression and treatment outcomes.

To investigate the gut microbiota and breast cancer, two clinical cohorts were profiled (using a range of sequencing and bioinformatics approaches) and additional mechanistic in vitro and in vivo studies were also undertaken. First, a local Norfolk cohort was established – BEAM, with the aim of longitudinally profiling newly diagnosed breast cancer patients (1 control and 35 breast cancer patients, as of 30 June 2023), however study recruitment was severely impacted due to the SARS-Cov-2 pandemic. My initial analysis indicated no significant shifts in microbiome profiles in the limited number of patients profiled, however I was able to establish a large culture collection through untargeted culturing. I obtained 298 strains from 50 different species which were whole genome sequenced and phylogenetically characterised. This work also led to the discovery and detailed description of one novel genus and one novel species - Allocoprobacillus halotolerans gen. nov., sp. nov and Coprobacter tertius sp. nov.

Concurrent to BEAM, the oral and gut microbiota samples from a phase 2a clinical trial (KELLY) that had been completed were processed, sequenced, and analysed which led to the creation of the CALADRIO study. The KELLY trial had one arm where all patients received treatment, a chemotherapeutic and immunotherapeutic. Overall, treatment did not cause significant gut or oral microbiota perturbations, which is usually indicative of drug-related microbiota toxicity. Differential analysis indicated that clinical benefit was driven, in part, by gut-associated Bacteroides fragilis. Further in vitro studies indicated a product present in the cell-free supernatant of B. fragilis led to greater cellular stress in breast cancer cells, but it did not result in complete cell death.

Bifidobacterium, generally considered a beneficial gut-associated bacterium, was consistently in the top ten most abundant genera of the gut microbiota in the BEAM and CALADRIO study. Thus, to define if Bifidobacterium was mechanistically associated with breast cancer outcomes, a Bifidobacterium longum subsp. longum isolate was selected and used as a live oral supplementation in a murine breast cancer model that was also treated with chemotherapy (cyclophosphamide). Oral supplementation resulted in larger primary tumours than cyclophosphamide alone suggesting that oral supplementation interfered with treatment efficacy. Genomic screening of the isolate showed that it possessed aldehyde dehydrogenase which is known to inactivate cyclophosphamide.

These data allowed me to explore how the gut microbiota of breast cancer patients may link to treatment outcomes and indicated both positive (e.g., B. fragilis) and negative (e.g., B. longum subsp. longum) impacts. Translating it into the clinic, such findings could provide avenues for improving efficacy of anti-cancer therapeutics. To test these further in vivo studies could be conducted to determine how candidate bacterial strains could influence the immune system in the context of breast cancer and building on those findings in vitro studies would investigate the intricacies of the gut-immune axis. Overall, my thesis outputs highlight the complex interactions between the microbiota and their host, and suggest new avenues for biomarker and therapy development, particularly in breast cancer.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Chris White
Date Deposited: 19 Dec 2023 09:57
Last Modified: 19 Dec 2023 09:57
URI: https://ueaeprints.uea.ac.uk/id/eprint/94002


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